Ethers of n-alkyl-3-hydroxypiperidine and salts thereof



limited States Patent 2,83Lild2 ETHERS UL PLALZKYLdQQYDROXYPIPERIDINEAND @ALTE) THEREGF John H. Biol, Milwaukee, Wis assignor to LakesideLaboratories, line, a corporation of Wisconsin No Drawing. ApplicationFebruary 27, 1956 Serial No. 567,754 r 6 Claims. (U. 260-2943} [OR Nwherein R is an alkyl group of 1 aryl group preferably which ismonocyclic, an arallryl group wherein the allryl moiety is a lower alkyland the aryl is preferably monocyciic, N lower alkyl-B-piperidyl,3-piperidyl, N-aralkyl-B-piperidyl wherein the alkyl moiety is a lowerallryl and the aryl moiety is monocyclic, N-acyl-3-piperidyl andZ,3-cli-(N-alkyl-3-piperidyloxy) phenyl groups wherein the alltyl moietyis a lower alkyl, and R is hydrogen and lower allryl groups, and saltsthereof.

The N-ailtyl-3-piperidyl others may be conveniently produced by-thcfollowing reactions:

(a) The condensation of the sodium or potassium salt of an Nallcyl-P)-hydroxypioeridine with an appropriate alkyl or aralkyl halide;

(b) The reaction of an 1 -allryl-Shydroxypiperidine with an alkyl oraralkyl halide in the presence of a strong base such as triethylamine,sodium amide or lithium amide; or

(c) The condensation of an appropriate sodium alcoholate with anN-allryl-S-halopiperidine.

The described reactions are readily effected under liquid reactionconditions preferably comprising an inert organ ic solvent such asxylene, toluene and benzene. Elevated reaction temperatures, such as thereflux temperature, complete the reaction in about 1 to 12 hours.Following completion of the reaction, the desired N-alkyl-S- plperidylether may be recovered by conventional procedures.

Typical N-alltyl-3shydroxypiperidines which may be used are those inwhich the alkyl group contains 1-8 carbons, such as methyl, ethyl,propyl and butyl as well 'a's branched chain alkyl groups likeisopr'opyl and t-butyl.

through carbons, an

in place of the 3-hydroxypiperidines the corresponding 3-halopiperidinesmay be used having similar N-alkyl groups and preferably bromine orchlorine as the S-halo substituent.

Allcyl halides which may be used as reactants are those of 1-10 carbons,straight or branched chained, as Well as cyclic allzyls, and in whichthe halogen is bro mine, chlorine or iodine. Arallcyl halides may beused in which the allryl moiety is a lower allzyl of 1-8 carbons and thearyl group is monocyclic such as a phenyl or nuclear substituted phenylgroup. To produce the aryl derivatives sodium or potassium salts of thecorresponding hydroxy substituted aryls, such as phenol, may beemployed. By reacting an N-alkyl-3-hydroxypiperidine with anN-alkyl-3-halopiperidine there is produced anIJ-alkyl-3-(N-alkyl-3'piperidyl) piperidyl ether; if the alkyl groupsare the same, symmetrical di-rz-alltyl- 3-piperidyl ethers are formed.

Representative of the compounds which are provided by this invention areN-ethyl3-piperidyl ethyl ether, N-propyl-3-pipcridyl butyi other,hT-butyi-- pipericlyl hexyl ether, N-ethyl3-piperidyl benzyl ether,N-methyl- 3-piperidyl phenethyl ether, di-N-ethyl-B-piperidyl ether,di-N-pentyl-3-piperidyl. ether and the like. The production of othersuch compounds is shown in the examples.

Production of similar ethers of Z-hydroxypiperidine which areunsubstituted at the cyclic nitrogen is achieved under similarconditions and with the same reactants with the exception that thecyclic nitrogen is protected with a group which may be cleavedsubsequent to the reaction. Acyl groups derived from menu carboxylicacids such as formyl, acetyl, propionyl and benzoyl groups may beconveniently employed to protect the cyclic nitrogen. After the desiredothers are formed the protecting acyl groups may be removed byhydrolysis such as with alcoholic caustic, preferably at an elevatedtemperature such as at reflux. Recovery of the product is achieved byconventional procedures.

Ty'picai compounds so produced are E-piperidyl methyl ether, 3-pieridylethyl ether, Bqolperidyl hexyl ether, 3-piperidyl n-octyl ether,3-piperidyl n-nonyl ether, 3-piperidyl benzyl ether, 3-piperidylphcnethyl other, 3-piperidyl phenyl ether and di-3-piperidyl other.

Acid addition salts of these and related compo-- are formed bycontacting the 3-piperid" mineral or organic acid such as hydroch' furicacid, formic acid, acetic acid, citric a maleic acid, fumaric acid,phosphoric acid, tartaric acid, hen: zoic acid, cinnamic acid, succ JllCacichmandelicacid and so forth.

, Quaternary ammonium salts areformed by contacting alkyl, aralkyl,allrenyl, allrynyl and aralkenyl est mineral and organic acids with theNoubstituted fi-p idyl others, preferably in the presence of an org 1'solvent. Some compounds which may be: reacted with the ethersto formquaternary ammonium salts are methyl bromide, methyl sulfate, benzylchloride, propargyl bro mide, methyl iodide and the like.

The compounds of this invention are: useful anti,- spasmodic compoundsand function as ganglionic blocking agents. The salts are preferred forsuch uses since they are much more water soluble than the free bases.For such therapeutic uses nontoxic salts are employed;

Examples of the new compounds and their preparation are as follows:

EXAMPLE I A. N-methyl-B-piperidyl ethyl ether, and its methabromide saltTo 5.75 g. (0.25 mole) of molten sodium metal in 150 cc. dry toluene wasadded 28 g. (0.24 mole) of N- methyl-3-hydroxypiperidine. The mixturewas stirred and refluxed until most of the sodium had reacted. To thehot solution of the sodium salt was added 39 g. (0.25 mole) of ethyliodide with stirring and refluxing. Stirring and refluxing werecontinued for eight hours. The reaction mixture was extracted withdilute aqueous hydrochloric acid, the aqueous acid extract saturatedwith potassium hydroxide, the alkaline mixture extracted with ether andthe ether extract dried with potassium carbonate. The ether was removedby distillation and the product collected at 42-45 C. (4.5 mm.) yield 17g. (50%).

Analysis.--Calcd. for C H NO: N, 9.78. Found: N,

To 11.0 g. (0.077 mole) of the basic ether dissolved in 50 cc. ofisopropyl alcohol was added 7.3 g. (0.077 mole) of methyl bromide. Theproduct was precipitated by the addition of 10 cc. of anhydrous ether,collected by filtration and recrystallized from isopropyl alcohol; yield7 g., M. P. 168-169 C.

Analysis.-Calcd. for 1-1 BrNO: Br, 33.61; N, 5.88. Found: Br, 33.60; N,5.86.

Other new compounds prepared by essentially the same method as set forthin Example I have the following structural formulae:

B. N-methyl-3-piperidyl 4-phenylbutyl ether and its hydrobromide salt C.N-2'-phenylethyl-S-piperidyl methyl ether and its methobromide salt U0on:

N III-CHzBr CHaCHad: CHzCH2 EXAMPLE II N-methyl-3-piperidyl phenyl etherand its methobromide salt To 7.8 g. (0.20 mole) of sodium amide in 100cc. of toluene was added with stirring 18.8 g. (0.20 mole) of phenol.The mixture was slowly heated 80 C., at which temperature a vigorousevolution of ammonia took place. After the reaction had subsided, themixture was stirred and refluxed for three hours. The solution wascooled to room temperature and 26.7 g. (0.20 mole) ofN-methyl-3-chloropiperidine in 50 cc. of toluene added. The reactionmixture was stirred and refluxed for twenty-four hours, filtered hot andthe filtrate extracted with dilute hydrochloric acid. The aqueous acidsolution was saturated with potassium hydroxide and extracted withether. The ethereal extract was dried with potassium carbonate anddistilled. The product boiled at 4849 C. (12 mm.); yield 32 g. (83%).

Analysis.Calcd. for CHHIBNO: N, 7.28. N, 7.27. I

To a solution of 9.6 g. (0.05 mole) of the basic ether in 50 cc.isopropyl alcohol was added 6.4 g. (0.067 mole) methyl bromide. Thesolution was seeded and crystallization allowed to proceed at roomtemperature. The crys- OCHa Found 4 talline product was collected byfiltration and recrystallized twice from isopropyl alcohol; yield 2.5 g.(18%), M. P. 192-193 C.

Analysis.-Calcd. for C H B1'NO: Br, 27.88; N, 4.88. Found: Br, 27.68; N,4.95.

EXAMPLE III 1,2,3-tris-(N-ethyl-3-piperidyloxy)-benzene ether and itsmethobromide salt 0 o I? N\ out-on. (E g-CH: 0mm 0 f) l N\ CHr-C CgCHI031B:

l N\ urn-cm C(rCH: other To 12.6 g. (0.10 mole) of pyrogallol in 250 cc.dry xylene was added 6.9 g. (0.30 mole) lithium amide. The mixture wasstirred and heated at 135-140 C. for four hours. To the hot solution wasadded,44.1 g. (0.30 mole) of N-ethyl-3-chloropiperidine. The mixture wasstirred and heated at 135-140 C. for six hours. Darco was then added,the mixture stirred and heated for another hour, cooled and clarified byfiltration. The filtrate was extracted with dilute aqueous hydrochloricacid. The acid extract was made strongly alkaline with solid potassiumhydroxide, the alkaline mixture extracted with ether and the etherextract dried with potassium carbonate. The ether was removed bydistillation and the product collected at 208-210 C. (0.05 mm.); yield16.5 g.

Analysis.-Calcd. for C H N O N, 9.15. Found: N, 9.12.

To 2.3 g (0.005 mole) of base in 25 cc. anhydrous isopropyl alcohol wasadded 2.85 g. (0.030 mole) CH Br and the mixture allowed to stand at 30C. for four days. The solution was treated with Darco, boiled for a fewminutes, filtered through Celite and anhydrous ether added to filtrateuntil precipitation of a gummy solid was complete. The ether wasdecanted, and the solid rubbed under fresh ether until crystalline,yield 2.4 g., M. P. indefinite, slow decomposition starting at C.

Analysis.-Calcd. for C3QH54BI'3N303I BI', 32.30; N, 5.66. Found: Br.33.35; N, 5.00.

EXAMPLE IV A. Di-N-methyl-3-piperidyl ether and its dimethobromide saltN 15: IIL-CHaB! III-CRIB:

CH: CH:

ether and saturated with solid potassium hydroxide. The alkaline mixturewas repeatedly extracted with ether and the ether extracts dried withpotassium carbonate. The ether was distilled and the residuefractionated in vacuo. The product was collected at 121-122 C. (9 mm.);yield 14 g. (29%).

Analysis.-Calcd. for C H N O: N, 13.21. Found: N, 13.12.

To 10.1 g. (0.048 mole) of the base in 100 cc. isopropyl alcohol wasadded 9.0 g. (0.096 mole) of methyl bromide. There was an immediateformation of a precipitate which was collected by filtration, yield 7 g.(37%); M. P. 246 C. dec.

Analysis.-Calcd. for C H Br- N O: Br, 39.80; N, 6.97. Found: Br, 39.95;N, 6.99.

Other new compounds prepared by essentially the same method as set forthin Example IV are as follows:

B. Di-N-ethyl-3-piperidyl ether and its dihydrochloride salt.

C. Di-N-2-phenethyl-3-piperidyl ether and its dihydrochloride anddimethobromide salts.

EXAMPLE V N-methyl-3-piperidyl nonyl ether and its hydrochloride salt Ina 300 ml. 3-necked round bottom flask equipped with mechanical stirrer,reflux condenser with potassium hydroxide drying tube, thermometer, andmantle, place 23.0 g. (0.2 mole) N-methyl-3-hydroxypiperidine in 100 ml.anhydrous toluene. Add 7.8 metal slowly with slow speed stirring at atemperature of 60-70 C. After of the potassium was added the materialbecame gelatinous so 50 ml. toluene was added and the temperature raisedto that of reflux. The remaining potassium was added and the solutionstirred 2.4 g. (0.01 mole) N-methyl-3-piperidyl nonyl ether wasdissolved in ml. anhydrous ethyl ether and acidifie d with etherealhydrochloric acid. The white precipitate was collected by anhydrousfiltration and dried. M. P. 83-86"; 1.7 g.; 63% yield.

Analysis.-Calcd. for C H ClNO: Cl, 12. 81; N, 5.05.

Found: Cl, 13.03; N, 5.10.

EXAMPLE VI N-ethyl-3-piperidyl nonyl ether and its hydrochloride salt Ina 500 ml. three-necked round-bottom flask equipped with mechanicalstirrer, reflux condenser with potassium hydroxide drying tube,thermometer and mantle, place 25.7 g. (0.2 mole) N-ethyI-B-hydroxypiperidine in 200 m1. anhydrous toluene. Add 7.8 g. 0.2 mole) potassiummetal slowly with slow speed stirring, then stir at reflux temperaturefor three hours. Then 41.4 g. (0.2 mole) n-nonyl bromide was addeddropwise with stirring and the mixture stirred and refluxed twenty-fourhours. The potassium bromide was filtered off and the filtrate extractedthree times with 100 ml. portions of ethyl ether (discard) and thenneutralized and made strongly alkag. (0.2 mole) potassium line withsolid potassium hydroxide with cooling, then extracted three times withml. portions of ethyl ether, extracts combined and dried over anhydrouspotassium carbonate and fractionally distilled. B. P.=100-l06 (less than0.5 mm); 23.3 g.; 45.6% yield.

Analysis.--Calcd. for C H NO: N, 5.49. Found: N, 5.59.

2.55 g. (0.01 mole) N-methyl-3-piperidyl nonyl ether was dissolved in100 ml. anhydrous ethyl ether and acidified to pH 3 with etherealhydrochloric acid. The white precipitate was collected by anhydrousfiltration and dried. M. P. 113-115 .C.

Analysis.-Calcd. for C H ClNO: Cl, 12.19; N, 4.80. Found: Cl, 12.23; N,4.95.

EXAMPLE VII 3-piperidyl nonyl ether A mixture containing 0.15 mole ofN-acetyl-3-hydroxypiperidine, 0.15 mole of sodium metal and 200 ml. ofdry toluene is refluxed for two hours. To this mixture is then added0.15 mole of n-nonyl bromide and refluxing continued for ten hours. Thereaction mixture is clarified by filtration and the filtrate subjectedto distillation in vacuo. To the distillate is added 100 ml. of 20%methanolic potassium hydroxide in 100 ml. of ethanol and the mixturerefluxed for 3 hours. After filtration the filtrate is concentrated todryness, the residue suspended in water, extracted with ether, the etherextract dried with K CO and then subjected to fractional distillation invacuo to recover 3-piperidyl n-nonyl ether.

In place of n-nonyl bromide there may be used N-acetyl-3-chloropiperidine to form di-N-acetyl-B-piperidyl ether whichmay be hydrolyzed to di-B-piperidyl ether.

The foregoing description is given for clearness of understanding onlyand no unnecessary limitations are to be understood therefrom, for somemodifications will be obvious to those skilled in the art.

What is claimed is:

1. A member of the group consisting having the formula J-OR N ofcompounds wherein R is a member of the group consisting of alkyl groupsof 1 through 10 carbons, phenyl, phenyl-lower alkyl groups, N-loweralkyl-3-piperidyl, 3-piperidyl, N- acyl-3-piperidyl wherein the acylgroup is derived from a lower carboxylic acid,2,3-di-(N-alkyl-3-piperidyloxy) phenyl groups wherein the alkyl moietyis a lower alkyl, and R is a member of the group consisting of hydrogen,lower alkyl groups, and acyl groups derived from lower carboxylic acids,and acid addition and quaternary ammonium salts thereof.

2. N-methyl-3-piperidyl phenyl ether.

3. 1,2(3-tris-(N-ethyl-3-piperidyloxy)-benzene ether.

4. Di-N-methyl-3-piperidyl ether.

5. N-methy1-3-piperidyl nonyl ether.

6. Di-3 piperidyl ether.

References Cited in the file of this patent UNITED STATES PATENTS2,479,843 Knox Aug. 23, 1949 OTHER REFERENCES Paul et al.: Bull. Soc.Chim., France, for 1947, pp. 341-345.

U. S. DEPARTMENT OF COMMERCE PATENT OFFICE I CERTIFICATE OF CORRECTIONPatent Noc 2,831,862 John H. Biel April 22., 1958 It is hereby certifiedthat error appears in the printed specification of the above numberedpatent requiring correction and that the said Let oers Patent shouldread as corrected below.

Column 6, line 59, for "l,2(3-tris-" read 1,2,3-trise Signed. and sealedthis 10th day of June 1958.

(SEAL) Attest K i AMNE ROBERT c. WATSON Attesting Officer Camissioner ofPatents

1.A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS HAVING THE FORMULA